Duodenal and gastric ulcers, known collectively as peptic ulcers, are localized erosions of the mucous membrane of the duodenum or stomach, respectively, which expose the underlying layers of the gut wall to the acid secretions of the stomach and to the proteolytic enzyme pepsin. They are believed to be caused by autolysis which is caused by an imbalance between offensive factors, such as acid or pepsin, and defensive factors, such as resistance of the mucous membrane, mucilage secretion, bloodstream or control of the duodenum. Peptic ulceration is the most common disease of the gastro-intestinal tract and it is estimated that approximately 10 to 20% of the adult male population will experience at some time in their lives.
Peptic ulcers are cured or prevented by medical treatment, in principle, and many pharmacotherapies have been suggested, some with high degrees of success.
Clinically useful modialities include H-.sub.2 -blockers, such as cimetidine and ranitidine, as anti-ulcer agents. It has been noted, more recently, that inhibitors of H.sup.+ -K.sup.+ -ATPase, an enzyme specifically present in the parietal cells of the stomach, can effectively inhibit the secretion of gastric acid in mammals, including man, therefore it has been expected that a new class of anti-ulcer agents from this viewpoint will come into existance. More specifically, a wide variety of compounds having a benzimidazole structure have been proposed. Among these compounds is Omeprazole, currently under active development, as the most promising compound; see U.S. Pat. Nos. 4,337,257; 4,255,431; and 4,508,905. These patents describe compounds with a methoxy group in the 4-position of the pyridine ring. Omeprazole, having the formula: ##STR1## and further 2-(4-methoxyethoxypyridine-2-yl)methylsulfinyl-5-methyl-1H-benzimidazole in the working examples thereof.
Related benzyimidazole-type compounds having anti-ulcer activities are described in published application GB 2,134,523A. More specifically, compounds in which the 4-position of the pyridine ring is substituted with an alkoxyalkoxy group with each alkoxy group containing 1-2 carbons are described. Example 157 of this patent describes 2-(3,5-dimethyl-4-methoxyethoxypyridine-2-yl)methylsulfinyl-5-phenyl-1H-be nzimidazole. Other substitutions on various positions of the benzyl and pyridine rings are also described.
Biological tests reported in tables 4 and 5 of this published application report significant biological effects on gastric acid secretion, both in isolated cells and in laboratory animals, when the 4-position on the pyridine ring is substituted with a methoxy group.
Additional benzimidazole-type compounds, in which the substituent at the 4-position on the pyridine ring is a benzyloxy group, are described in European patent application 0,167,943.